Nitrous acid-catalyzed nitration of 4-bromo-2,5-dichlorophenol. Observation of an unusually facile rearrangement of a 4-bromo-2-nitrophenol during nitration

Full text of DOI:10.1021/jo960290v

J . Org. Chem. 1996, 61, 6425-6429
6425
of water and filtration of the resulting crystalline solid.
However, if greater than 1.0 equiv of nitric acid was
added, the concentration of 3 rapidly decreased with the
production of three additional compounds. The major
product from the reaction in the presence of excess nitric
acid was identified as 2-bromo-3,6-dichloro-4-nitrophenol
(5). Varying amounts of 3, 2,4-dinitro-3,6-dichlorophenol
(6), and 2,4-dibromo-3,6-dichlorophenol (7) were also
obtained.
Nitr ou s Acid -Ca ta lyzed Nitr a tion of
4-Br om o-2,5-d ich lor op h en ol. Obser va tion
of a n Un u su a lly F a cile Rea r r a n gem en t of a
4-Br om o-2-n itr op h en ol d u r in g Nitr a tion
David A. Conlon,* J oseph E. Lynch,
Frederick W. Hartner, J r., Robert A. Reamer, and
R. P. Volante
Process Research, Merck Research Laboratories, Merck and
Co., Inc. P.O. Box 2000, Rahway, New J ersey 07065-0900
Resu lts a n d Discu ssion
Received February 13, 1996
Careful control of the nitration reaction conditions
allowed the isolation of the desired primary product,
4-bromo-3,6-dichloro-2-nitrophenol (3) without formation
of side products as shown in Table 1. However, a slight
excess of nitric acid led to rapid formation of the isomeric
phenol 5.
Mass spectral and elemental analysis of 3 and 5
indicate these compounds are isomeric, and with the
proton spectra only showing one aromatic CH and a
broad phenolic resonance, 13C NMR was used to distin-
guish these structures.6-8
In addition, the UV spectra were very helpful in
assigning the structures of the nitrophenols. The position
of the nitro group in nitrophenols can be differentiated
by their UV spectrum. The 4-nitrophenols, 5 and 6,
absorb out to longer wavelengths.9
There are many reports of nitro groups replacing
halogens during the nitration of halophenols (Zincke
nitration)10 and one reported case of the migration of a
halogen from the 4 position to the 2 position during
nitration,11 although it appears to be more common in
halo anisoles (Reverdin reaction).12,13 In an attempt to
understand the rapid disappearance of the desired prod-
uct, we studied the rearrangement of 3 under a variety
of controlled conditions (Table 3).
In tr od u ction
During the development of a synthesis of the non-
nucleoside, HIV-1 specific reverse transcriptase inhibitor,
L-697,661 (1)1,2 we required easy access to the known
2-aminophenol (2).2 There were several possible routes3
to the aminophenol 2, but we chose to examine the
nitration of the readily available 4-bromo-2,5-dichlo-
rophenol (4),4 to generate the 2-nitrophenol 3, expecting
the 4-bromo substituent to undergo hydrogenolysis con-
comitant with reduction of the nitro group to the amine.
We report our observations on the unusual kinetic
behavior of this nitration and the facile rearrangement
of the product, 4-bromo-3,6-dichloro-2-nitrophenol (3), to
the apparently thermodynamically more stable 2-bromo-
3,6-dichloro-4-nitrophenol (5). The nitration of 4 in
propionic acid with 70% HNO3 displayed a highly vari-
able induction period. At one extreme, an equimolar
solution of 4 and HNO3 (0.5 M) could be stirred at 30 °C
for 24 h with no detectable reaction occurring. In other
experiments an obvious reaction took place during ad-
dition of nitric acid to the phenol; the previously colorless
solution turned yellow then orange-red accompanied by
an increase in temperature of several degrees. It is well
known that nitrous acid catalyzes the nitration of phenols
by nitric acid.5 Indeed, addition of a catalytic amount of
NaNO2 (0.2 mM) to a solution of phenol 4 (0.5 M), H2-
SO4 (0.12 M), and HNO3 (0.05 M) in propionic acid
reproducibly initiated the nitration reaction. Once initi-
ated, the reaction was then very fast; nitric acid could
essentially be titrated into the reaction mixture with
excellent results (Figure 1).
In addition to the nitration reagents (NaNO2/HNO3),
NaNO2 in propionic acid alone could initiate the rear-
rangement. When the reaction with NaNO2 was re-
peated in a degassed solution of propionic acid, the
rearrangement was significantly slowed, strongly sug-
gesting the causative agent was an oxidation state of
(6) Stothers, J . B. in Carbon-13 NMR Spectroscopy; Academic
Press: New York, 1972, p 197.
(7) Ersnt, L.; Wray, V.; Chertkov, V. A.; Sergeyev, N. M. J . Magn.
Reson. 1977, 25, 123-139.
After sufficient nitric acid was added to give 98-99%
conversion of 4, the product, 4-bromo-3,6-dichloro-2-
nitrophenol (3), could be isolated in 94% yield by addition
(8) The difference in the chemical shift of a bromine bearing (-5.4
ppm) versus a nitro bearing (+19.6 ppm) aromatic carbon (relative to
benzene at 128.7 ppm),6 combined with 1H-13C spin-spin coupling
constant data permits assignment of these isomers.7 Although three-
bond 1H-13C couplings constants are the largest in aromatic systems,
two-bond and even four-bond couplings can be observed when elec-
tronegative substituents are on the coupling pathway. In 3, the
bromine bearing carbon at 111.6 ppm has a long-range proton splitting
of 4.7 Hz, consistent with a two-bond coupling pathway. The nitro
bearing carbon at 141.5 ppm, which is slightly broadened, has a long-
range coupling of less than 2 Hz. Complementary data are observed
in 5 where the bromine bearing carbon at 115.4 ppm is a 1.8 Hz
doublet, due to a four-bond coupling pathway. The nitro bearing carbon
at 140.4 ppm, is a 4.3 Hz doublet, consistent with a two-bond pathway.
These data, along with the rest of the 1H-13C coupling constants in
Table 2, permit unequivocal assignments of these structures.
(9) Pecsok, R. L.; Shields, L. D.; Cairns, T.; McWilliam, I. G. Modern
Methods of Chemical Analysis, 2nd ed.; J ohn Wiley & Sons: New York,
1976; p 240.
(1) Goldman, M. E. Discovery and Development of 2-Pyridone HIV-1
Reverse Transcriptase Inhibitors. The Search for Antiviral Drugs;
Adams, J ., Merluzzi, V. J ., Eds.; Birkhauser: Boston, 1993; pp 105-
127.
(2) Saari, W. S.; Hoffman, J . M.; Wai, J . S.; Fisher, T. E.; Rooney,
C. S.; Smith, A. M.; Thomas, C. M.; Goldman, M. E.; O'Brien, J . A.;
Nunberg, J . H.; Quintero, J . C.; Schleif, W. A.; Emini, E. A.; Stern, A.
M.; Anderson, P. S. J . Med. Chem. 1991, 34, 2922-2925. Grotta, H.
M.; Page, T. F., J r.; Riggle, C. J .; Manian, A. A. J . Heterocycl. Chem.
1967, 4, 611.
(3) We initially prepared 2 from 2,5-dichlorophenol via a one-pot
sulfonation, nitration, desulfonation procedure, which gave the 2-ni-
trophenol 21, followed by hydrogenation. Although this procedure
provided
2 in a reasonable yield, the temperature required for
desulfonation (>150 °C) is dangerously close to the initiation temper-
ature of a significant exothermic decomposition of the reaction mixture.
This procedure was deemed unsafe to practice on a preparative scale.
(4) Ross, F. USP 3,728,403; Apr 17, 1973; Chem. Abstr. 1973, 79
(11), 66003r.
(10) Raiford, L. C.; Miller, G. R. J . Am. Chem. Soc. 1933, 55, 2125-
2131.
(11) Robertson, P. W. Trans. 1908, 93, 793.
(5) Olah, G. A.; Malhotra, R.; and Narang, S. C. Nitration Methods
and Mechanisms (Organic Nitro Chemistry Series); Feuer, H., Ed.; VCH
Publishers, Inc.: New York, 1989; pp 129-134.
(12) Robinson, G. M. J . Chem. Soc. 1916, 109, 1078.
(13) Perrin, C. L.; Skinner, G. A. J . Am. Chem. Soc. 1971, 93, 3389-
3394.
S0022-3263(96)00290-3 CCC: $12.00 © 1996 American Chemical Society

6426 J . Org. Chem., Vol. 61, No. 18, 1996
Notes
Sch em e 1
Ta ble 2. 13C Ch em ica l Sh ifts a n d 1H-13C Sp in -Sp in
Cou p lin g Con sta n ts in 3 a n d 5a
3
5
3
3
C1
C2
C3
C4
C5
C6
146.0, J ) 8.2 Hz
155.7, J ) 8.1 Hz
4
4
141.5, J < 2 Hz
115.4, J ) 1.8 Hz
3
3
123.4, J ) 10.4 Hz
126.5, J ) 9.0 Hz
2
2
111.6, J ) 4.7 Hz
140.4, J ) 4.3 Hz
134.5,1J ) 174.8 Hz
126.0, J ) 174.8 Hz
1
2
2
123.2, J ) 4.9 Hz
120.0, J ) 5.1 Hz
a
Spectra run in DMSO-d6, digital resolution for coupling
constant data ) 0.4 Hz/pt.
Ta ble 3. Rea r r a n gem en t of 3 w ith Differ en t Ad d itives
additivea
time (h)
3 (%)
5 (%)
6 (%)
7 (%)
none
NaNO2
NaNO2
NaNO2
NaNO2
NO2BF4
NO2SbF6
0
1
2
3
3
3
3
3
99.3
21.6
1.3
0.2
22.8
50.9
49.4
5.4
2.7
1.6
8.7
42.1
0.3
30.7
28.6
27.1
6.3
0.2
3.9
0
3.1
0
b
14.9
7.2
5.2
15.0
1.4
0.2
2.8
4.7
b
b
1.3
c
65.2
89.6
90.3
81.2
36.1
c
F igu r e 1. Equivalents of nitric acid versus area % of 3.
c
c
Sch em e 2
NOBF4
brominec
0.8
a
0.1 equiv of additive added to a 0.5 M solution of 3 in propionic
acid. Atmospheric oxygen was not excluded. c Degassed using
b
freeze-pump-thaw.
Sch em e 3
rophenol (9) was produced under the reaction conditions
with excess nitric acid (1.2 equiv). This demonstrates
that the 4-bromo substituent or another weakly bonded
substituent is required for this rearrangement to occur.
The observation that 4-chlorophenols are not reactive
may be attributed to the difference in the homolytic bond
dissociation energy for chlorine and bromine carbon
bonds (ca. 12 kcal/mol).15
Ta ble 1. Rea r r a n gem en t of 3 In th e P r esen ce of Excess
Nitr ic Acid
HNO3 (equiv)
time (h)
3 (%)
5 (%)
6 (%)
7 (%)
We were interested in the relationship between the
rearrangement and the mechanism of the nitration.
0.98
1.02
1.02
5
5
20
94.9
57.2
<0.1
<0.1
8.2
56.3
0
19.4
22.8
0
0
16
Reaction of 4-bromo-2,5-dichlorophenol (4) with N2O4
<0.1
in propionic acid resulted in the formation of 3 with the
nitro group introduced cleanly into the ortho position.
Again the same observation was made as in the nitrous
acid-catalyzed nitration; as long as excess starting mate-
rial remained no rearrangement was observed, but once
4 was consumed the initially formed product 3 quickly
rearranged to a mixture of 3, 5, 6, and 7. Significantly,
the selective ortho nitration by N2O4 was as equally
effected in hexane solvent as in propionic acid. The exact
reason for the selectivity in this radical reaction is not
completely understood.
nitrogen derived from nitrite rather than nitrite itself.
Milligan14 determined that sodium nitrite in trifluoro-
acetic acid liberates nitric oxide. If we assume that nitric
oxide is also formed in our system, then we can propose
that in the presence of oxygen, nitric oxide is oxidized to
nitrogen dioxide. Other oxidation states of nitrogen
including nitronium and nitrosonium salts were exam-
ined and were found to have a small noncatalytic effect
on 3. Any mechanism proposed for this interesting
rearrangement must account for the formation of all of
the reaction products. A separate study with 2,4,5-
trichlorophenol (8) showed that only 2-nitro-3,4,6-trichlo-
(15) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in
Organic Chemistry, 2nd ed.; Harper & Row: New York, 1981; p 147.
(16) Dinitrogen tetraoxide (N2O4) is known to exist in equilibrium
with the monomeric nitrogen dioxide (NO2).
(14) Milligan, B. J . Org. Chem. 1983, 48, 1495-1500.

Notes
J . Org. Chem., Vol. 61, No. 18, 1996 6427
Sch em e 4
Sch em e 5
There are many similarities between nitrous acid-
catalyzed nitrations and nitrations performed in the
presence of nitrogen dioxide. Eberson17 and Hartshorn18
have both reported similar products from nitrous acid-
catalyzed nitrations and nitrations involving nitrogen
dioxide. We propose that the first step in the nitrous
acid-catalyzed nitration is the formation of nitrogen
dioxide. In this reaction nitric acid acts only as a source
of nitrogen dioxide as first proposed by Titov.19
Ta ble 4. P r od u ct Mixtu r es Obta in ed by Tr ea tm en t of 3,
6, or 7 w ith Ch a in Rea ction In itia tor s
compound additive time (h) 3 (%) 5 (%) 6 (%) 7 (%)
3
3
6
6
7
7
none
NBS
none
NBS
none
NaNO2
0
0.08
0
24
0
1
99.7
31.7
<0.1
2.1
<0.1
6.7
0.1
56.0
<0.1
40.3
<0.1
13.9
0.2
2.6
98.6
46.5
<0.1
<0.1
0
7.3
<0.1
2.3
97.7
76.8
can occur, but that chlorophenols are much less reactive.5
Addition of nitrogen dioxide to the 4 position of 12
generates the cyclohexa-2,5-dienone 13.
Loss of bromine atom from 13 generates 14, the
phenoxy radical of the dinitrophenol 6. Addition of
bromine radical to the 2 position of 14 generates the
cyclohexa-2,4-dienone 15 that can lose nitrogen dioxide
and generate the phenoxy radical 16. Addition of the
bromine radical to the 2 position of 12 and subsequent
loss of nitrogen dioxide generates 18, which is the
phenoxy radical of the dibromophenol 7.
Consideration of this mechanism yields a number of
predictions: first, the rearrangement of 3 should be
catalyzed by bromine atom as well as by NO2 (see Table
3). Second, starting with either 6 or 7 and addition of
either bromine atom or NO2 should result in a similar
rearrangement. Treatment of 3 with NBS in the pres-
ence of AIBN in propionic acid led to extensive rear-
rangement (Table 4); likewise, treatment of 6 with NBS/
AIBN and 7 with NaNO2 led to the product mixtures
shown in Table 4.
Comparison of compound composition before and after
treatment in Table 4 demonstrates that the rearrange-
ment can be accomplished from several starting points.
First, treatment of the bromonitrophenol 3 with NBS
results in the formation of 5-7. The dinitrophenol 6
rearranges under NBS catalysis, and the dibromophenol
7 rearranges when treated with sodium nitrite. This
evidence strongly supports a chain mechanism because
regardless of the starting point the same products are
formed (Scheme 6).
As nitrogen dioxide is a free radical, the next step
would be the abstraction of the phenolic hydrogen to
generate a phenoxy radical. There are CIDNP studies
that support the formation of a phenoxy radical during
nitrous acid-catalyzed nitrations of nitrophenol.20 In
addition, the 4-methyl-2,6-di-tert-butylphenoxy radical
has been observed by EPR during the reaction of 4-meth-
yl-2,6-di-tert-butylphenol with nitrogen dioxide.21 Re-
cently, Coombes22 has reported a study of the mechanism
of the reaction of 2,4,6-tri-tert-butylphenol and 2,4,6-tri-
tert-butylphenoxy radical with nitrogen dioxide. This
suggested to us that a radical reaction may in fact be
operative, and we propose the mechanism as shown in
Scheme 4.
Two assumptions, inherent in this mechanism, are that
nitrogen dioxide addition to 10 shows both high positional
selectivity and also high chemoselectivity such that no
further reaction of 3 occurs in the presence of even low
concentrations of 4.
A radical chain reaction can be written for the rear-
rangement of 12 to the phenoxy radicals of 5, 6, and 7
as shown in Scheme 5. There are numerous reports,
consistent with our observations, that during the nitra-
tion of halophenols ipso attack at an iodine or bromine
(17) Eberson, L.; Radner, F. Acta Scand. B 1985, 39, 343-356.
(18) Hartshorn, M. P.; Martyn, R. J .; Robinson, W. T.; Sutton, K.
H.; Vaughan, J .; White, J . M. Aust. J . Chem. 1983, 36, 1589-1602.
(19) Titov, A. I. Tetrahedron 1963, 19, 557-580.
(20) Clemens, A. H.; Ridd, J . H. Sandall, J . P. B. J . Chem. Soc.,
Perkin Trans. 2 1984, 1667-1672. Clemens, A. H.; Ridd, J . H.; Sandall,
J . P. B. J . Chem. Soc., Chem. Commun. 1983, 343-344.
(21) Brunton, G.; Cruse, H. W.; Whittle, A. Tetrahedron Lett. 1979,
1093-1094.
(22) Coombes, R. G.; Diggle, A. W.; Kempsell, S. P. Tetrahedron Lett.
1993, 34, 8557-8560.
Curiously, none of the monobromo or mononitro com-
pounds (4, 20-22) were formed (Scheme 7).
A mechanism for the nitration of 4 involving both
nitrosonium ion and NO2 cannot be excluded since one
can argue any solution containing NO2 also contains at
least a small equilibrium concentration of nitrosonium
ion. The fact that nitrosonium ion is a poor electrophile
and 4 is a relatively electron poor substrate argues

6428 J . Org. Chem., Vol. 61, No. 18, 1996
Notes
added. The temperature of the reaction mixture increased to
-15 °C. The solution was cooled to -20 °C and then allowed to
warm to ambient temperature over 2 h. Additional NBS was
added (0.55 g, 3.1 mmol), and the reaction mixture was stirred
at 23 °C for 1.75 h. The reaction mixture was concentrated in
vacuo, and the wet yellow solids were partitioned between ethyl
ether (200 mL) and water (200 mL). The separated organic layer
was washed with water (200 mL), dried over anhydrous mag-
nesium sulfate, and concentrated in vacuo. A yellow solid (18.7
g) was isolated. This material (1H-NMR) contained 95.6% of 7
and 4.4% of 4. The yield corrected for purity is 90.9%. An
analytical sample was prepared by recrystallizing 7 (18.1 g) from
hexanes (84 mL): mp 97-98 °C (lit. mp 99-100 °C);23 1H NMR
(250 MHz, CDCl3) δ 7.63 (s, 1 H); 6.04 (s, 1 H); 13C NMR (250
MHz, CDCl3) δ 149.3, 134.1, 132.0, 119.4, 113.1, 112.2. Anal.
Calcd for C6H2Br2Cl2O: C, 22.46; H, 0.63; Cl, 22.10. Found: C,
22.46; H, 0.61; Cl, 22.25.
Sch em e 6
4-Br om o-3,6-d ich lor o-2-n itr op h en ol (3). A 50 mL three-
neck flask equipped with a magnetic stirrer and a thermocouple
was charged with 4 (4.0 g, 16.54 mmol), propionic acid (28 mL),
and sulfuric acid (228 µL, 4.13 mmol) and warmed to 30 °C. A
solution of 70% nitric acid (298 µL, 5.6 M, 1.67 mmol) in
propionic acid and 16 µL of an aqueous sodium nitrite solution
(0.41 M, 6.6 µmol) were added, and the temperature of the
reaction solution increased to 33 °C. Additional nitric acid
solution (2.44 mL, 13.73 mmol) was added over a 10 min period
maintaining the reaction temperature between 30-35 °C during
the addition.
Sch em e 7
The reaction mixture was added dropwise to a cold (10-15
°C) saline solution (20 g sodium chloride/228 mL water) over a
10 min period. An orange solid was isolated by filtration,
washed with water (3 × 5 mL), and dried in vacuo with a
nitrogen sweep. The weight of 3 isolated was 4.46 g (94%). An
analytical sample was prepared by recrystallization from cyclo-
hexane: mp 110-112 °C; 1H NMR (399.87 MHz, DMSO-d6) δ
11.1 (v br, 1 H), 8.11 (s, 1H); 13C NMR (100.56 MHz, DMSO-d6):
δ 146.0, 141.5, 134.5, 123.4, 123.1, 111.6. MS (EI, 70 eV) m/z
285 (M+). Anal. Calcd for C6H2BrCl2N2O3: C, 25.12; H, 0.70;
N, 4.88; Cl, 24.72. Found: C, 25.19; H, 0.66; N, 4.71; Cl, 24.77.
Nitr a tion of 4 w ith Nitr ogen Dioxid e in P r op ion ic Acid .
Nitrogen dioxide was bubbled into a solution of 4 (0.83 M) in
propionic acid for 10 s. Assay by HPLC after 10 min indicated
the formation of 3 (57 A%) with remaining 4 (43 A%). Continued
addition of nitrogen dioxide resulted in complete conversion of
4 to 3 and eventually in the formation of dinitrophenol 6.
Nit r a t ion of 4 w it h Nit r ogen Dioxid e in Hexa n es.
Nitrogen dioxide was bubbled into a saturated hexane solution
of 4 (0.03 M) for 1 min. The solution was stirred at room
temperature overnight and assayed by HPLC that indicated the
formation of 3 (28 A%) with remaining 4 (60 A%).
against a mechanism involving nitrosation. The possible
role of nitrosonium ion in the rearrangement mechanism
is less clear especially since nitrosonium ion alone cannot
initiate this rearrangement (Table 3) and 3 is an even
more electron poor substrate. Furthermore, the fact that
both the nitrous acid-catalyzed nitration of 4 and the
nitration of 4 with N2O4 have the same reaction profile
suggests similar reaction manifolds.
It is significant that this rearrangement shows high
positional selectivity in both propionic acid and hexane;
only ortho- and para-substituted products are formed.
The nitration of 4 by N2O4 under nonpolar conditions
suggests that radical nitration may indeed be capable of
high positional selectivity at least with some substrates
(phenols), and that a radical nitration mechanism is
worthy of more serious consideration.
2-Br om o-3,6-d ich lor o-4-n itr op h en ol (5). A 20 mL scintil-
lation vial equipped with a magnetic stir bar was charged with
1.33 g (4.64 mmol) of 3, 10 mL of propionic acid and 0.022 g
(0.32 mmol) of sodium nitrite and capped. The hazy red-orange
solution was stirred at room temperature for 2 h and then poured
into saturated sodium chloride solution (10 mL). The mixture
was extracted twice with ethyl ether (10 mL) and the separated
ether solution was dried over anhydrous sodium sulfate. An
orange solid was isolated by concentration in vacuo (1.27 g). This
solid was recrystallized three times from cyclohexane to yield
Exp er im en ta l Section
Gen er a l. Materials were obtained from commercial sources
and used without purification. HPLC analyses were performed
on a Hewlett Packard Series 1050 and/or 1090 Liquid chromato-
graph equipped with a UV detector (210 nm), and a Zorbax RX-
C8 reverse phase analytical column (4.6 cm × 250 mm). The
mobile phase was acetonitrile/water, and the flow rate was 1.5
mL/min. The area percentage has been corrected for detector
response, and the yields were determined with an internal
standard. NMR spectra were recorded on Bruker AM-250, AM-
400, and AMX-400 spectrometers. Chemical shifts are reported
in ppm and for 1H spectra were calibrated against the residual
protium of the solvent: CHCl3 (δ ) 7.27) and DMSO-d5 (δ )
2.50). Chemical shift references for 13C spectra are CDCl3 (δ )
77.0) and DMSO-d6 (δ ) 39.5). All coupling constants are
reported in hertz (Hz). Melting points were determined on a
Thomas Hoover melting point apparatus and are uncorrected.
Microanalysis was performed by Quantitative Technologies, Inc.
4-Bromo-2,5-dichlorophenol (4), 6-bromo-2,5-dichlorophenol
(10), and 2,4-dibromo-3,6-dichlorophenol (7) are known com-
pounds.4
1
0.86 g (65%) of 5: mp 129-130 °C dec; H NMR (399.87 MHz,
DMSO-d6): δ 11.34 (br s, 1 H), 8.27 (s, 1 H); 13C NMR (100.56
MHz, DMSO-d6) δ 155.7, 140.3, 126.6, 125.9, 120.0, 115.4. MS
(EI, 70 eV) m/z : 285 (M+). Anal. Calcd for C6H2BrCl2N2O3:
C, 25.12; H, 0.70; N, 4.88; Cl, 24.72. Found: C, 25.16; H, 0.65;
N, 4.66; Cl, 24.52.
2,4-Din itr o-3,6-d ich lor op h en ol (6). A 50 mL two-neck
flask equipped with a condenser, nitrogen inlet, thermocouple,
and a magnetic stir bar was charged with 1.63 g (10 mmol) of
2,5-dichlorophenol, 22 mL of propionic acid, 140 µL (2.5 µmol)
of sulfuric acid, and 150 µL (2.4 mmol) of nitric acid. Solid
sodium nitrite (20 mg, 0.29 mmol) was added to the colorless
solution that quickly developed a yellow color and gas evolution
was noted.
2,4-Dibr om o-3,6-d ich lor op h en ol (7). A 500 mL three-neck
flask equipped with an overhead mechanical stirrer, thermo-
couple, and a nitrogen inlet was charged with 10.0 g (61.3 mmol)
of 2,5-dichlorophenol, 200 mL of methanol, and 42 µL of
hydrobromic acid (48% aqueous). The solution was cooled to -20
°C, and solid N-bromosuccinimide (21.8 g, 122.6 mmol) was
A solution of 70% nitric acid (1.5 mL, 24 mmol) in propionic
acid (5 mL) was added over 5 min with a temperature increase
(23) Fox, D. L.; Turner, E. E. J . Chem. Soc. 1930, 1853-1867.

Notes
J . Org. Chem., Vol. 61, No. 18, 1996 6429
from 20 °C to 35 °C. The reaction mixture was allowed to cool
to 20 °C and was stirred overnight.
charged with a magnetic stir bar and 0.054 mmol of one of the
following; NaNO2, NO2BF4, NO2SbF6, NOBF4, or Br2. The tubes
were capped with three-way stopcocks, and the apparatus was
degassed using freeze-pump-thaw techniques. The apparatus
was vented to dry nitrogen, and the solution of 3 was transferred
to the other side of the apparatus and mixed. Samples were
removed at timed intervals for HPLC assay, and the assay
results are included in Table 3.
Rea r r a n gem en t of 3 w ith NBS/AIBN. A 1 dram screw cap
vial was charged with 0.1723 g (0.6 mmol) of 3, 0.0213 g (1.26
mmol) of NBS, 0.0001 g (0.00006 mmol) of AIBN, and 500 µL of
propionic acid. This solution was stirred at room for 5 min and
assayed by HPLC. The results are reported in Table 4.
Rea r r a n gem en t of 6 w ith NBS/AIBN. A 1 dram screw cap
vial was charged with 0.0265 g (0.1 mmol) of 6, 0.0211 g (0.12
mmol) of NBS, 0.0052 g (0.03 mmol) of AIBN, and 500 µL of
propionic acid. This solution was stirred at room temperature
overnight and assayed by HPLC. The results are reported in
Table 4.
Rea r r a n gem en t of 7 w ith Na NO2. A 1 dram screw cap vial
was charged with 0.1414 g (0.44 mmol) of 7, 0.1076 g (1.56 mmol)
of sodium nitrite, and 2 mL of propionic acid. This solution was
stirred at room temperature for 1 h and assayed by HPLC. The
results are reported in Table 4.
Deter m in a tion of th e Rela tive Resp on se F a ctor s for 3,
5, 6, a n d 7. A 1 dram screw cap vial was charged with 0.040
mmol of 3, 0.040 mmol of 5, 0.041 mmol of 6, and 0.040 mmol of
7 and dissolved in CD3CN. Comparison of the areas from the
integrated 1H-NMR spectrum with the area determined by
HPLC gave the relative response factors for 3, 5, 6, and 7 of
1.00, 1.81, 2.32, and 1.03, respectively.
The reaction mixture was poured into a cold sodium chloride
solution, and an orange solid was collected by filtration. The
solid was washed with water and dried in vacuo. The product
6 was isolated in 65% yield (1.64 g). An analytical sample was
prepared by recrystallization from cyclohexane: mp 142-144
°C; 1H NMR (250 MHz, CDCl3) δ 8.21 (s, 1 H); 13C NMR (100.56
MHz, DMSO-d6) δ 156.9, 142.5, 130.5, 127.8, 122.6, 119.4. MS
(EI, 70 eV) m/z 252 (M+). Anal. Calcd for C6H2Cl2N2O5: C,
28.48; H, 0.80; N, 11.08; Cl, 28.03. Found: C, 28.42; H, 0.85;
N, 10.78; Cl, 27.86.
2-Nitr o-3,4,6-tr ich lor op h en ol (9). A 50 mL two-neck flask
equipped with a condenser, nitrogen inlet, thermocouple and a
magnetic stir bar was charged with 4.01 g (20.3 mmol) of 2,4,5-
trichlorophenol and 25 mL of propionic acid. The solution was
warmed to 30 °C and 278 µL (5 mmol) of sulfuric acid, 125 µL
(2 mmol) of nitric acid and 16 µL of a 0.5 M aqueous sodium
nitrite solution (8 µmol) were added to the solution, which
quickly developed a yellow color and exothermed to 35 °C.
Neat 70% nitric acid (1.4 mL, 22.4 mmol) was added over 1h
while maintaining the temperature between 30-35 °C. The
reaction mixture was allowed to cool to 20 °C, poured into a
sodium chloride solution (8 g/110 mL) and an oil precipitated.
The mixture was extracted with ethyl ether, washed with brine
and dried over magnesium sulfate. The solvent was removed
in vacuo to give 3.94 g of 9 (80% yield). An analytical sample
was prepared by recrystallization from cyclohexane: mp 90-
91 °C; 1H NMR (250 MHz, CDCl3) δ 7.65 (s, 1 H), 7.56 (bs, 1 H);
13C NMR (100.56 MHz, CDCl3) δ 146.0, 138.1, 132.6, 125.9,
125.0, 121.7. MS (EI, 70 eV) m/z 241 (M+). Anal. Calcd for
C6H2Cl3NO3: C, 29.72; H, 0.83; N, 5.78; Cl, 43.87. Found: C,
29.90; H, 0.88; N, 5.54; Cl, 43.66.
Ack n ow led gm en t. We are grateful to Mr. Robert
M. Purick and Mr. Donald F. Storey for technical
assistance and Mr. Gregory J . McManemin for mass
spectroscopy work.
Rea r r a n gem en t of 3. Gen er a l P r oced u r e. One side of a
J -tube reaction vessel24 was charged with 1 mL of a 0.5 M
solution of 3 (0.5 mmol) in propionic acid and the other side was
(24) Rowland, R. G. Ph.D. Thesis, University of Rochester, Roches-
ter, NY, 1989.
J O960290V